Mechanism of Action of Antisense RNA in Eukaryotic Cells

Abstract

For many years, an appealing strategy to target the inhibition of expression of specific cellular or viral genes has been to express within cells RNA transcripts that have the potential to form duplex RNA hybrids with their target messages (1). Although there are numerous examples in the literature of the successful application of antisense strategy, the many failures and frustrations have been less well documented. Recent work from a number of laboratories, and from a number of different experimental directions, has begun to provide a molecular framework for understanding how antisense RNA works within cells. Understanding these “rules” for antisense RNA holds the promise to aid in the future design and implementation of more effective antisense approaches. In this chapter we will discuss some of the current knowledge about how antisense RNA works. It has become apparent in the past several years that the formation of double-stranded RNA (dsRNA), triggers a variety of cellular effects that depend not only on the length of the RNA duplex, but also on its intracellular location and on the cell type (1). These effects include activation of the protein kinase (PKR) and RNase L pathways, interferon responses, covalent modification of dsRNAs, and regulation of specific gene expression such as genomic imprinting. Most recently, the discovery of the remarkable phenomenon of dsRNA-induced RNA interference (RNAi) in cells of higher eukaryotes has become one of the great breakthroughs in studying the regulation of gene expression (2–6). KeywordsAntisense TranscriptHepatitis Delta VirusTranscriptional Gene SilenceNuclear RetentionHigh Eukaryotic CellThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.